Anti-pro-N-cadherin antibodies and methods of treating pathological fibrotic conditions and tumor cells

Abstract

Humanized antibody to a pathologically mislocated form of N-cadherin detects and eliminates cells that express the protein extracellularly. These cells are found in fibrotic conditions within heart, lung, and liver, as well as kidney, skin, and other organs effected by fibrosis. The antibody does not affect cells with normal, subcellular location of the protein.

We claim: 
     
       1. A humanized antibody which specifically binds to pro-N-cadherin in its pro-domain, said humanized antibody comprising:
 framework portions of a human antibody; and 
 six complementarity determining regions (CDRs) of a mouse antibody, wherein the CDRs are SEQ ID NO: 22-27 or SEQ ID NO: 28-33. 
 
     
     
       2. The humanized antibody of  claim 1  wherein the human antibody is an antibody isotype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4. 
     
     
       3. The humanized antibody of  claim 1  wherein the humanized antibody is conjugated to a cytotoxic moiety. 
     
     
       4. The humanized antibody of  claim 3  wherein the cytotoxic moiety is selected from the group consisting of a chemotherapeutic drug, a toxin, and a radioisotope. 
     
     
       5. A method of treating a human with a pathological fibrotic condition to reduce number of pathological fibrotic cells in the human, said method comprising: administering to the human a humanized antibody that binds to pro-N-cadherin in its pro-domain, whereby number of pathological fibrotic cells is reduced; wherein the humanized antibody comprises framework portions from a human antibody; and six complementarity determining regions (CDRs) from a mouse antibody, wherein the CDRs are SEQ ID NO: 22-27 or SEQ ID NO: 28-33. 
     
     
       6. The method of  claim 5  wherein the pathological fibrotic condition is a disease of an organ selected from the group consisting of heart, lung, skin, kidney, and liver. 
     
     
       7. The method of  claim 5  wherein the pathological fibrotic condition is selected from the group consisting of pulmonary fibrosis, radiation-induced lung injury, cystic fibrosis, idiopathic pulmonary fibrosis, liver cirrhosis, atrial fibrosis, and endomyocardial fibrosis. 
     
     
       8. The method of  claim 5  wherein the pathological fibrotic condition is selected from the group consisting of scleroderma, Crohn's disease, and arthrofibrosis. 
     
     
       9. A method of treating a human with a tumor condition to reduce number of tumor cells in the human, said method comprising: administering to the human a humanized antibody that binds to pro-N-cadherin in its pro-domain, whereby number of tumor cells in the human is reduced; wherein the humanized antibody comprises framework portions from a human antibody and six complementarity determining regions (CDRs) from a mouse antibody; and wherein the CDRs are SEQ ID NO: 22-27 or SEQ ID NO: 28-33. 
     
     
       10. A chimeric antibody which specifically binds to pro-N-cadherin in its pro-domain, said chimeric antibody comprising:
 framework portions from a non-murine antibody; and six complementarity determining regions (CDRs) from a mouse antibody, wherein the CDRs are SEQ ID NO: 22-27 or SEQ ID NO: 28-33. 
 
     
     
       11. The chimeric antibody of  claim 10  wherein the framework portions comprise up to 10 amino acid residue substitutions relative to the non-murine antibody. 
     
     
       12. The chimeric antibody of  claim 10  that comprises heavy and light chain variable regions comprising SEQ ID NO: 18-19 or 20-21. 
     
     
       13. The chimeric antibody of  claim 10  that has an affinity for pro-N-cadherin that is at least as great as that of a murine antibody comprising the same six CDRs. 
     
     
       14. The chimeric antibody of  claim 10  that as an affinity for pro-N-cadherin that is at least two times as great as that of a murine antibody comprising the same six CDRs.